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Human fused NKG2D–IL-15 protein controls xenografted human gastric cancer through the recruitment and activation of NK cells

NKG2D公司 癌症研究 CD8型 细胞毒性T细胞 MHC I级 免疫疗法 白细胞介素12 生物 癌症免疫疗法 黑色素瘤 白细胞介素15 癌细胞 免疫学 癌症 白细胞介素 免疫系统 体外 细胞因子 生物化学 遗传学
作者
Yan Chen,Bei Chen,Ti Yang,Weiming Xiao,Qian Li,Yanbing Ding,JI Ming-chun,Xiaoqun Ge,Weijuan Gong
出处
期刊:Cellular & Molecular Immunology [Springer Nature]
卷期号:14 (3): 293-307 被引量:46
标识
DOI:10.1038/cmi.2015.81
摘要

Interleukin (IL)-15 plays an important role in natural killer (NK) and CD8+ T-cell proliferation and function and is more effective than IL-2 for tumor immunotherapy. The trans-presentation of IL-15 by neighboring cells is more effective for NK cell activation than its soluble IL-15. In this study, the fusion protein dsNKG2D-IL-15, which consisted of two identical extracellular domains of human NKG2D coupled to human IL-15 via a linker, was engineered in Escherichia coli. DsNKG2D-IL-15 could efficiently bind to major histocompatibility complex class I chain-related protein A (MICA) of human tumor cells with the two NKG2D domains and trans-present IL-15 to NK or CD8+ T cells. We transplanted human gastric cancer (SGC-7901) cells into nude mice and mouse melanoma cells with ectopic expression of MICA (B16BL6-MICA) into C57BL/6 mice. Then, we studied the anti-tumor effects mediated by dsNKG2D-IL-15 in the two xenografted tumor models. Human dsNKG2D-IL-15 exhibited higher efficiency than IL-15 in suppressing gastric cancer growth. Exogenous human dsNKG2D-IL-15 was centrally distributed in the mouse tumor tissues based on in vivo live imaging. The frequencies of human CD56+ cells infiltrated into the tumor tissues following the injection of peripheral blood mononuclear cells into nude mice bearing human gastric cancer were significantly increased by human dsNKG2D-IL-15 treatment. Human dsNKG2D-IL-15 also delayed the growth of transplanted melanoma (B16BL6-MICA) by activating and recruiting mouse NK and CD8+ T cells. The anti-melanoma effect of human dsNKG2D-IL-15 in C57BL/6 mice was mostly decreased by the in vivo depletion of mouse NK cells. These data highlight the potential use of human dsNKG2D-IL-15 for tumor therapy.Cellular & Molecular Immunology advance online publication, 14 September 2015; doi:10.1038/cmi.2015.81.
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